Paclitaxel is a diterpene taxane found in very low concentration in the bark of Pacific yew tree Taxus brevifolia. A number of semi-synthetic strategies have been developed for its synthesis from more readily available 10-DAB. However, the taxane nucleus is highly prone to degradation and semi-synthetic crude materials are often contaminated with structurally similar impurities. As a result, elaborate purification procedure using HPLC are required to produce pharmaceutical grade material. Thus, it becomes highly desirable to develop alternative routes, which involves minimal degradation.
In general, synthetic strategy for the semi-synthesis of paclitaxel/docetaxel comprises
a) selective acylation/protection at similarly reactive C-7 and C-10 hydroxyl groups. Among the 1, 7, 10 and 13-hydroxyl groups in 10-DAB, the order of reactivity is 7>10>13>1. This requires selection of appropriate protecting groups, which can be put selectively and removed selectively under mild condition. Until recently, trialkylsilyl group, particularly triethylsilyl has been considered as the protecting group of choice for C-7 hydroxyl group. U.S. Pat. No. RE 34,277 (reissue of U.S. Pat. No. 4,924,011) describes conversion of 10-DAB into 7-triethylsilyl-10-deacetylbaccatin III, which is then acetylated at the 10-position with an acetylating agent. However, this process requires use of 5 to 20 equivalents of costly silylating agent and yields of each these steps were around 85% only. In U.S. Pat. No. 6,130,336, Kim et al., describes use of trichloroacetyl halides to protect C-7 hydroxyl group selectively followed by acetylation at 10-position with acetyl bromide. On the other hand, in U.S. Pat. No. 6,500,966 simultaneous protection of both C-7 and C-10 hydroxyl group is carried out with trichloroacetyl anhydride. Recently, we have explored the use of haloalkonyl as protecting groups (U.S. Provisional Patent Application. No 60/311,077). These haloalkonoyl groups undergo hydrolysis faster than unsubstituted alkonoyl groups and their deprotection causes minimum degradation. Also, these acid chlorides are cheaper and more easily available in comparison to trichloroacetyl halides used in U.S. Pat. No. 6,130,336 or trichloroacetic anhydride used in U.S. Pat. No. 6,500,966.
b) selective esterification of 13-hydroxyl group with a suitably protected N-benzoylphenylisoserine. It is known that esterification step proceeds to completion with cyclic forms of α-hydroxy-β-amidoarylcarboxylic acids such as oxazolidine carboxylic acid. Furthermore, when cyclic forms of C-13 side chain is used, no 2′-epimers is obtained as side product. Use of oxazolidine side chain generally requires protection of the 3-position of the side chain with a substituted carbonyl group as the amino group at 3-position tends to react with carboxylic acid group of another oxazolidine molecule thereby retarding the coupling reaction. It has been observed that nitrogen of oxazolidine ring does not require protection when 2-position is substituted with trihalomethyl or phenyl substituted with a trihalomethyl group. Oxazolidine carboxylic acid having two halomethyl substituents at 2-position and an unprotected nitrogen atom has been reported to undergo smooth coupling with a suitably protected 10-DAB (U.S. Pat. No. 6,130,336).
c) conversion of side chain precursor part into side chain and removal of the protecting groups from baccatin part. These reaction conditions should be mild in nature to afford final material in high yield with few side products.
Most of the nitrogen protecting groups used in oxazolidine carboxylic acid requires harsh acidic condition or hydrogenolysis for their removal and thus do not fulfil the criteria mentioned above. Also removal of nitrogen protecting group leads to an amine intermediate, which is not so stable and results in crude which are difficult to purify. Obviously it would be better if we could use benzoyl or tert. butoxycarbonyl group as the nitrogen protecting group in the oxazolidine side chain and open the oxazolidine ring under mild condition so that these groups are retained.
Thus, U.S. Pat. No. 5,637,723, issued to Rhone Poulenc Rorer S. A. in 1997, described an oxazolidine carboxylic acid, which incorporated benzoyl group as the nitrogen-protecting group. Consequently, the coupled product upon deprotection does not require to be benzoylated. An alternative approach has been described in U.S. Pat. No. 6,500,966, wherein a coupled product is first deprotected to remove the protecting trichloroacetyl groups on the deacetylbaccatin moiety followed by optional acetylation at C-10 hydroxyl group and subsequent acid hydrolysis of the oxazolidine ring.
Herein, the Applicants have described new intermediates for taxoid anti-cancer drugs, their process of synthesis and process for synthesis of paclitaxel and docetaxel using them in Scheme 1.